Use of triazinetrione sulfones for combating coccidiosis

ABSTRACT

The present invention relates to the use of specific derivatives of triazinetriones for controlling coccidioses in livestock, especially pigs.

[0001] The present invention relates to the use of specific derivativesof triazinetriones for controlling coccidioses in livestock.

[0002] Coccidioses are infections which occur frequently in livestockand thus, for example, subclinical infections caused by protozoa of thegenera coccidia, sarcosporidia and toxoplasma in. pigs are spreadworldwide. Isospora suis infections, for example, have, however, only inrecent years been recognized as the cause of piglet diarrhoea and beenresearched very intensively. As a rule, infection takes place from themother sow to the piglets or from piglet to piglet via oocysts each ofwhich contain two sporocysts each with two sporozoites. The parasiticstages multiply in the epithelial cells of the villi of the smallintestine, but extraintestinal stages have also been detected in theliver, spleen and lymph nodes. The clinical appearance of the diseaseincludes a necrotic, inflammatory destruction of the intestinalepithelial cells and thus extensive interference with digestion andabsorption. An acute disease is characterized by a watery, whitish oryellowish foul-smelling diarrhoea which usually occurs in week 2-3 oflife. Infected piglets have a reduced weight gain. The treatment andtherapy of the disease have not to date been adequately solved.Antibiotics are ineffective; although sulphonamides are recommended,therapy is usually too late. Other possibilities of treatment arecontradictory: it was not possible to prevent disease by administeringmonensin, amprolium or furazolidone to experimentally infected piglets.In recent investigations it was possible to identify in some units,despite good hygiene, Isospora suis in up to 92% of all litters.

[0003] It is known from a number of publications, inter alia GermanOffenlegungsschriften 27 18 799, 25 090 37, 25 323 63, 24 137 22, WO99/62519 that various derivatives of triazinetriones are suitable forcontrolling coccidioses in livestock.

[0004] It is also known from a number of publications, for exampleDriesen et al., Australian Vet. J., 72 (4) 139-141, 1995; Rommel et al.,Int. J. of Parasit., 17, 639-647, 1987; Haberkorn and Mundt., Prakt.Tierarzt, 69 (4), 46, 49-51, 1988) that toltrazuril, a particulartriazinetrione derivative, is suitable for treating coccidiosis(Isospora suis) in pigs.

[0005] Because of the wide variety of requirements to be met by modempharmaceuticals, for example concerning level of activity, duration ofaction, spectrum of action, range of applications, toxicity, combinationwith other active ingredients, combination with formulation aids orsynthesis, because of the possible occurrence of resistance, thedevelopment of such substances cannot, however, ever be regarded ascomplete, and there is a continuing great need for novel compounds whichhave advantages, at least in some aspects, over known compounds.

[0006] It has now been found that triazinetrione sulphones of theformula (I)

[0007] in which

[0008] R¹ represents halogenoalkyl,

[0009] R² represents alkyl, alkoxy, halogen or SO₂N(CH₃)₂, and theirphysiologically tolerated salts, have a very good coccidiocidal effecttogether with astonishingly low mammalian toxicity.

[0010] The compounds of the formula (I) can be obtained by the processesdisclosed in German Offenlegungsschriften 27 18 799, 25 090 37, 25 32363, 24 137 22, WO 99/62519.

[0011] The compounds of the formula (I) show when used according to theinvention for treating coccidioses in livestock a mammalian toxicitywhich is surprisingly low compared with compounds known in the state ofthe art, and are therefore clearly superior to the known compounds inthis use.

[0012] Compounds of the formula (I) employed for the use in controllingcoccidioses in livestock are preferably those

[0013] in which

[0014] R¹ represents C₁-C₄-halogenoalkyl with 1 to 5 halogen atoms,

[0015] R² represents C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen or SO₂N(CH₃)₂,and their physiologically tolerated salts.

[0016] Compounds of the formula (I) particular preferably employedaccording to the invention are those in which

[0017] R¹ represents C₁-C₄ halogenoalkyl with 1 to 5 halogen atoms,

[0018] R² represents C₁-C₄-alkyl, and their physiologically toleratedsalts.

[0019] Compounds of the formula (I) very particularly preferablyemployed according to the invention are those in which

[0020] R¹ represents C₁-C₄ perhalogenoalkyl,

[0021] R2 represents methyl or ethyl, and their physiologicallytolerated salts.

[0022] In particular, the use of the compound of the formula

[0023] with the name ponazuril is very particularly preferred.

[0024] The compounds of the formula (I) may, where appropriate,depending on the nature and number of the substituents be in the form ofgeometric and/or optical isomers or regioisomers or mixtures of suchisomers of varying composition. Both the use of the pure isomers and ofthe mixtures of isomers are claimed according to the invention.

[0025] Compounds which are preferred, particularly preferred or veryparticularly preferred etc. are those which have the substituentsmentioned below as preferred, particularly preferred or veryparticularly preferred etc.

[0026] Preferred among the halogenoalkyl radicals indicated in thedefinition of R¹, including those mentioned as preferred, particularlypreferred, very particularly preferred, are in each case in turn thefluoroalkyl radicals.

[0027] The radical definitions and explanations stated above in generalor stated in preferred ranges can, however, also be combined as desiredwith one another, that is to say between the respective ranges andpreferred ranges.

[0028] The compounds according to the invention can for the useaccording to the invention against coccidiosis be converted into allconventional formulations and be administered in various administrationforms. Oral administrations are preferred in this connection, inparticular administration as oral aqueous suspension.

[0029] Preferred dosages are 1-500 mg of active ingredient per kg ofbody weight of the animal to be treated, particularly preferred dosagesare from 10 to 200 mg/kg and very particularly preferred dosages are20-100 mg/kg.

[0030] Preparations suitable for livestock are:

[0031] solutions such as solutions for injection, oral solutions,concentrates for oral administration after dilution, solutions for useon the skin or in body cavities, pour-on formulations, gels;

[0032] emulsions and semisolid preparations for oral or cutaneous useand for injection; examples of semisolid preparations are suspensions,pastes.

[0033] Formulations in which the active ingredient is processed in anointment base or in an oil-in-water or water-in-oil emulsion base;

[0034] solid preparations such as powders, premixes or concentrates,granules, pellets, tablets, boluses, capsules; aerosols and inhalations.

[0035] Solutions for injection are administered intravenously,intramuscularly and subcutaneously.

[0036] Solutions for injection are prepared by dissolving the activeingredient in a suitable solvent and possibly adding additions such assolubilizers, acids, bases, buffer salts, antioxidants, preservatives.The solutions are sterilized by filtration or, if necessary, preparedaseptically and bottled.

[0037] Solvents which may be mentioned are: physiologically toleratedsolvents such as water, alcohols such as ethanol, butanol, benzylalcohol, glycerol, propylene glycol, polyethylene glycols,N-methylpyrrolidone, glycerol formal, solketal(=isopropylideneglycerol), dimethylacetamide, 2-pyrrolidone, tetraglycol(=polyethylene glycol ether of tetrahydrofurfuryl alcohol) and mixturesthereof.

[0038] The active ingredients can, where appropriate, also be dissolvedin physiologically tolerated vegetable or synthetic oils suitable forinjection.

[0039] Solubilizers which may be mentioned are: solvents which promotethe dissolving of the active ingredient in the main solvent or preventits precipitation. Examples are polyvinylpyrrolidone, polyethoxylatedcastor oil, polyethoxylated sorbitan esters.

[0040] Examples of preservatives are: benzyl alcohol, trichlorobutanol,p-hydroxybenzoic esters, n-butanol, and organic acids with preservingproperties such as benzoic acid, propionic acid or sorbic acid and saltsthereof. The preservatives may, where appropriate, also be employed ascombination of two or more agents.

[0041] Oral solutions are used directly. Concentrates are used orallyafter previous dilution to the use concentration. Oral solutions andconcentrates are prepared as described above for injection solutions, itbeing possible to dispense with sterile operations.

[0042] Solutions for use on the skin or body cavities are poured on,painted on, rubbed in, sprayed on or used for dips. These solutions areprepared as described above for solutions for -injection. It isparticularly advantageous to add thickeners during preparation.

[0043] Thickeners are: inorganic thickeners such as bentonites,colloidal silica, aluminium monostearate, organic thickeners such ascellulose derivatives, polyvinyl alcohols and their copolymers,acrylates and methacrylates, xanthans.

[0044] Gels are applied to or spread on the skin or introduced into bodycavities. Gels are prepared by mixing solutions which have been preparedas described for solutions for injection with sufficient thickener toresult in a clear composition with an ointment-like consistency. Thethickeners applied are the thickeners indicated hereinbefore.

[0045] Pour-on formulations are poured or sprayed on to limited areas ofthe skin, in which case the active ingredient either penetrates throughthe skin and has a systemic action or is distributed on the surface ofthe body.

[0046] Pour-on formulations are prepared by dissolving, suspending oremulsifying the active ingredient in suitable solvents or mixtures ofsolvents which are compatible with skin. Further excipients such ascolorants, absorption-promoting substances, antioxidants, lightstabilizers, adhesives are added where appropriate.

[0047] Solvents which may be mentioned are: water, alkanols, glycols,polyethylene glycols, polypropylene glycols, glycerol, aromatic alcoholssuch as benzyl alcohol, phenylethanol, phenoxyethanol, esters such asethyl acetate, butyl acetate, benzyl benzoate;

[0048] Ethers such as alkylene glycol alkyl ethers such as dipropyleneglycol monomethyl ether, diethylene glycol monobutyl ether, ketones suchas acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons,vegetable or synthetic oils, DMF, dimethylacetamide,N-methylpyrrolidone, 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane.

[0049] Colorants are all colorants which are approved for use onlivestock and which can be dissolved or suspended.

[0050] Absorption-promoting substances are DMSO, spreading oils such asisopropyl myristate, dipropylene glycol pelargonate, silicone oils,fatty acid esters, triglycerides, fatty alcohols.

[0051] Antioxidants are sulphites or metabisulphites such as potassiummetabisulphite, ascorbic acid, butylated hydroxytoluene, butylatedhydroxyanisole, tocopherol.

[0052] Examples of light stabilizers are substances from the class ofbenzophenones or novantisolic acid.

[0053] Examples of adhesives are cellulose derivatives, starchderivatives, polyacrylates, natural polymers such as alginates, gelatin.

[0054] Emulsions can be used orally, cutaneously or as injection.

[0055] Emulsions are either of the water-in-oil type or of theoil-in-water type.

[0056] They are prepared by dissolving the active ingredient in onephase and homogenizing the latter with the assistance of suitableemulsifiers and, where appropriate, further excipients such ascolorants, absorption-promoting substances, preservatives, antioxidants,light stabilizers, viscosity-increasing substances.

[0057] Mention may be made of the following as hydrophobic phase (oils):paraffin oils, silicone oils, natural vegetable oils such as sesame oil,almond oil, castor oil, synthetic triglycerides such as caprylic/capricacid biglyceride, triglyceride mixture with vegetable fatty acids ofchain length C₈₋₁₂ or other specially selected natural fatty acids,partial glyceride mixtures of saturated or unsaturated, possibly alsohydroxyl group-containing fatty acids, mono- and diglycerides ofC₈/C₁₀-fatty acids.

[0058] Fatty acid esters such as ethyl stearate, di-n-butyryl adipate,hexyl laurate, dipropylene glycol perlargonate, esters of a branchedfatty acid of medium chain length with saturated fatty alcohols of chainlength C₁₆-C₁₈, isopropyl myristate, isopropyl palmitate,caprylic/capric esters of saturated fatty alcohols of chain lengthC₁₂-C₁₈, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate,ethyl lactate, waxy fatty acid esters such as artificial duck preengland oil, dibutyl phthalate, diisopropyl adipate, ester mixturesrelated to the latter inter alia.

[0059] Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol,cetylstearyl alcohol, oleyl alcohol.

[0060] Fatty acids such as, for example, oleic acid and mixturesthereof.

[0061] Mention may be made of the following as hydrophilic phase:

[0062] water, alcohols such as, for example, propylene glycol, glycerol,sorbitol and mixtures thereof.

[0063] Mention may be made of the following as emulsifiers: surfactants(including emulsifiers and wetting agents), such as

[0064] 1. nonionic, for example polyethoxylated castor oil,polyethoxylated sorbitan monooleate, sorbitan monostearate, ethylalcohol, glycerol monostearate, polyoxyethyl stearate, alkylphenolpolyglycol ether,

[0065] 2. ampholytic such as di-Na N-lauryl-β-iminodipropionate orlecithin,

[0066] 3. anionic such as Na-lauryl sulphate, fatty alcohol ethersulphates, mono/dialkyl polyglycol ether orthophosphoric estermonoethanolamine salt,

[0067] 4. cationic such as cetyltrimethylammonium chloride.

[0068] Further suitable excipients are:

[0069] viscosity-increasing and emulsion-stabilizing substances such ascarboxymethylcellulose, methylcellulose and other cellulose and starchderivatives, polyacrylates, alginates, gelatin, gum arabic,polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinylether and maleic anhydride, polyethylene glycols, waxes, colloidalsilica or mixtures of the substances mentioned.

[0070] Suspensions can be used orally, cutaneously or as injection. Theyare prepared by suspending the active ingredient in a liquid vehiclewhere appropriate with addition of further excipients such as wettingagents, antifoams, colorants, absorption-promoting substances,suspension stabilizers, preservatives, antioxidants, light stabilizers,humectants.

[0071] Mention may be made as preferred of suspensions which can beadministered orally and contain:

[0072] A) compounds of the formula (I) in concentrations of from 0.1 to30% by weight, particularly preferably from 1 to 10% by weight.

[0073] B) suspension stabilizers such as, for example, bentonites and/orxanthans in concentrations each of from 0.01 to 5% by weight,particularly preferably from 0.05 to 1% by weight.

[0074] C) where appropriate ionic or nonionic wetting agents inconcentrations of from 0.01 to 5% by weight, particularly preferablyfrom 0.1 to 0.5% by weight.

[0075] D) where appropriate antifoams based, for example, on siliconesin concentrations of from 0.01 to 5% by weight, particularly preferablyfrom 0.05 to 0.5% by weight.

[0076] E) where appropriate humectants in concentrations of from 1 to30% by weight, particularly preferably from 5 to 20% by weight.

[0077] F) where appropriate preservatives or else combinations thereofin concentrations of from 0.001 to 5% by weight, particularly preferablyfrom 0.1 to 0.5% by weight.

[0078] G) where appropriate acidic or basic substances in theconcentrations necessary to adjust the pH.

[0079] Liquid vehicles which may be mentioned are the solvents andhomogeneous mixtures of solvents mentioned hereinbefore as long as theyare pharmaceutically acceptable and the active ingredient or activeingredients dissolve therein to only a small extent or not at all. Wateris preferably used.

[0080] Wetting agents (dispersants) which may be mentioned for thesuspensions which can be administered orally are surfactants such as

[0081] 1. anionic such as Na lauryl sulphate, fatty alcohol ethersulphates, mono/dialkyl polyglycol ether orthophosphoric estermonoethanolamine salt, ligninsulphonates or dioctyl sulphosuccinate,

[0082] 2. cationic such as cetyltrimethylammonium chloride,

[0083] 3. ampholytic such as di-Na N-lauryl-β-iminodipropionate orlecithin,

[0084] 4. nonionic, for example polyethoxylated castor oil,polyethoxylated sorbitan monooleate, sorbitan monostearate, ethylalcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenolpolyglycol ether, Pluronic®.

[0085] Suitable antifoams are those based on silicones, for exampledimethicone or simethicone.

[0086] Suspension stabilizers which can be employed are, for example,the viscosity-increasing substances mentioned hereinbefore.

[0087] It is possible to employ conventional humectants, and exampleswhich may be mentioned are: propylene glycol, glycerol, sugar alcoholssuch as sorbitol, sugars such as sucrose.

[0088] Suitable preservatives are known to the skilled person; exampleshave already been mentioned hereinbefore. Organic acids with preservingproperties are preferably employed, such as, for example, benzoic acid,propionic acid or sorbic acid and salts thereof. The preservatives canalso be employed as combination of two or more agents, and a preferredexample which may be mentioned is a combination of sodium propionate andsodium benzoate.

[0089] Suitable acidic or basic substances for adjusting the pH areconventional pharmaceutically acceptable acids, bases and buffers.

[0090] Acids which may be mentioned are, for example: hydrochloric acid,citric acid and tartaric acid. Examples of bases which may be mentionedare: alkali metal hydroxides such as sodium hydroxide and potassiumhydroxide; alkali metal and alkaline earth metal carbonates such assodium carbonate, and amines, for example mono-, di- or triethanolamine.

[0091] Examples of suitable buffer systems are those based onphosphates.

[0092] The pH is preferably in the range from 2 to 10, in particular 3to 7.

[0093] The active ingredient is preferably employed in micronized formin the suspensions, normally in particle size distributions of from 0.1to 100 μm, preferably 1 to 50 μm.

[0094] Further excipients which may be mentioned are those indicatedhereinbefore.

[0095] Pastes can be administered orally or cutaneously. They differfrom the mobile to viscous suspensions and emulsions described above bytheir higher viscosity. Pastes containing ponazuril (=toltrazurilsulphone) have already been described in WO 99/62519.

[0096] Those which may be mentioned as preferred are pastes which can beadministered orally and contain compounds of the formula (I), which arecharacterized in that

[0097] a) the active ingredient is present in a particle size of 1×10⁻⁶m and a maximum particle size of 50×10⁻⁶ m in a concentration of 0.1-20%by weight,

[0098] b) polyacrylic acids with an acrylic acid content of from 56 to68% by weight and a molecular weight of about 3×10⁶, which areneutralized with alkali metal or alkaline earth metal bases, are presentin a concentration of 0.1-5% by weight,

[0099] c) where appropriate humectants are present in a concentration offrom 5 to 30% by weight,

[0100] d) where appropriate preservatives are present in a concentrationof from 0.01 to 0.5% by weight,

[0101] e) and the remainder in 100% by weight is made up with water.

[0102] The active ingredient is present in the said pastes preferably inconcentrations by weight of from 5% by weight to 20% by weight,particularly preferably from 10% by weight to 15% by weight.

[0103] The polyacrylic acids used in the said pastes are preferablyneutralized with alkali metal hydroxide or carbonate. Polyacrylic acidsare present in the formulation according to the invention inconcentrations by weight of from 0.2% to 1%, preferably of 0.5%. Theseare commercially available and known in pharmacopoeias for example underthe proprietary name Carbomer 934 P.

[0104] Preferred preservatives in the said pastes arepara-hydroxybenzoic esters (parabens) such as methyl 4-hydroxybenzoate,ethyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate. The preservativescan be employed singly or in combination for adequate preservation. Theyare normally present in concentrations of 0.01-0.5% by weight.

[0105] It is optionally possible for the said pastes also to containhumectants such as, for example, glycerol or 1,2-propylene glycol.Humectants are employed in concentrations by weight of from 5% to 30%,preferably from 10% to 20%.

[0106] The active ingredient is present in the said pastes in a particlesize of from 1 to 10×10⁻⁶ m, preferably from 1 to 5×10⁻⁶ m. The maximumof the particle size- is 50×10⁻⁶ m, preferably 30×10⁻⁶ m. The particlesizes are determined by laser scattering measurement (for example with aMalvern Mastersizer). The paste is obtained by mixing the individualcomponents. Its consistency can be altered by increasing or decreasingthe water content. A pasty consistency is desired. This permits oraladministration of the composition with suitable applicators such assyringes, tubes, spatulas etc.

[0107] To prepare solid preparations, the active ingredient is mixedwith suitable carriers, where appropriate with the addition ofexcipients, and converted into the desired shape.

[0108] Carriers which may be mentioned are all physiologically toleratedsolid inert substances. Inorganic and organic substances are used assuch. Examples of inorganic substances are sodium chloride, carbonatessuch as calcium carbonate, hydrogen carbonates, aluminium oxides,silicas, aluminas, precipitated or colloidal silicon dioxide,phosphates.

[0109] Examples of organic substances are sugars, cellulose, human andanimal foods such as milk powder, animal meals, ground and crushedgrains, starches.

[0110] Excipients are preservatives, antioxidants, colorants, which havealready been mentioned hereinbefore.

[0111] Further suitable excipients are lubricants and glidants such as,for- example, magnesium stearate, stearic acid, talc, bentonites,disintegration-promoting substances such as starch or crosslinkedpolyvinylpyrrolidone, binders such as, for example, starch, gelatin orlinear polyvinylpyrrolidone, and dry binders such as microcrystallinecellulose.

[0112] The active ingredients can also be in the form of theirencapsulated solid or liquid formulations mentioned above.

[0113] The active ingredients can also be used in the form of anaerosol. For this purpose, the active ingredient is finely dispersed ina suitable formulation under pressure.

[0114] It may also be advantageous to use the active ingredients informulations which release the active ingredient in a delayed manner.

[0115] The active ingredients are preferably administered together withthe feed and/or the drinking water.

[0116] The feed includes feedstuff ingredients of vegetable origin suchas hay, beets, cereals, cereals by-products, feedstuff ingredients ofanimal origin such as meat, fats, dairy products, bone meal, fishproducts, also feedstuff ingredients such as vitamins, proteins, aminoacids, for example DL-methionine, salts such as calcium carbonate andsodium chloride. The feed also includes supplementary, formulated andcompounded feedstuffs. These contain feed ingredients in a compositionwhich ensures a balanced diet in terms of energy and protein supply andthe supply of vitamins, mineral salts and trace elements.

[0117] The concentration of the active ingredients in the feed isnormally about 0.01 to 500 ppm, preferably 0.1 to 50 ppm.

[0118] The active ingredients can be added as such or in the form ofpremixes or feed concentrates to the feed.

[0119] Premixes and feed concentrates are mixtures of the activeingredient with a suitable carrier.

[0120] The carriers include feedstuff ingredients or mixtures thereof.

[0121] They may additionally contain further aids such as, for example,substances which control the flow properties and mixing properties, suchas, for example, silicas, bentonites, ligninsulphonates. It isadditionally possible to add antioxidants such as BHT or preservativessuch as sorbic acid or calcium propionate.

[0122] Concentrates for administration via the drinking water must beformulated so that a clear solution or a stable homogeneous suspensionis produced on mixing with the drinking water.

[0123] Suitable carriers are therefore water-soluble substances (feedadditives) such as sugars or salts (for example citrates, phosphates,sodium chloride, Na carbonate).

[0124] They may likewise contain antioxidants and preservatives.

[0125] The active ingredients are suitable, while having a surprisinglylow toxicity for warm-blooded species, for the control according to theinvention of parasitic protozoa which occur in livestock management andlivestock breeding among agricultural and breeding livestock, zoo,laboratory and experimental animals and pets. They are moreovereffective against all or individual stages of development of the pestsand against resistant and normally sensitive strains. Control of theparasitic protozoa is intended to reduce disease, deaths and reductionsin performance (for example in the production of meat, milk, wool,hides, eggs, honey etc) so that more economic and easier livestockmanagement is possible through use of the active ingredients.

[0126] The parasitic protozoa include:

[0127] Mastigophora (Flagellata) such as, for example, Trypanosomatidae,for example Trypanosoma brucei, T. gambiense, T. rhodesiense, T.congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T.simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, suchas, for example, Trichomonadidae, for example Giardia lamblia, G. canis.

[0128] Sarcomastigophora (Rhizopoda) such as Entamoebidae for exampleEntamoeba histolytica, Hartmanellidae for example Acanthamoeba sp.,Hartmanella sp.

[0129] Apicomplexa (Sporozoa) such as Eimeridae for example Eimeriaacervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E.arloingi, E. ashata, E. aubumensis, E. bovis, E. brunetti, E. canis, E.chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E.debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E.flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina,E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media,E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E.ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E.phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec., E.stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuemii,Globidium spec., Isospora belli, I. canis, I. felis, I. ohioensis, I.rivolta, I. spec., I. suis, Neospora caninum, N. hugesi, Cystisosporaspec., Cryptosporidium spec. such as Toxoplasmadidae for exampleToxoplasma gondii, such as Sarcocystidae for example Sarcocystisbovicanis, S. bovihominis, S. neurona, S. ovicanis, S. ovifelis, S.spec., S. suihominis such as Leucozoidae for example Leucozytozoonsimondi, such as Plasmodiidae for example Plasmodium berghei, P.falciparum, P. malariae, P. ovale, P. vivax, P. spec., such asPiroplasmea for example Babesia argentina, B. bovis, B. canis, B. spec.,Theileria parva, Theileria spec., such as Adeleina for exampleHepatozoon canis, H. spec.

[0130] In addition Myxospora and Microspora, for example Glugea spec.Nosema spec.

[0131] In addition Pneumocystis carinii, and Ciliophora (Ciliata) suchas, for example, Balantidium coli, Ichthiophthirius spec., Trichodinaspec., Epistylis spec.

[0132] The compounds according to the invention are also effectiveagainst protozoa which occur as parasites on insects. Those which may bementioned are parasites of the phylum Microsporida, in particular of thegenus Nosema. Particular mention may be made of Nosema apis in thehoneybee.

[0133] Protozoa which should be very particularly emphasized are thoseof the genera and species which lead to subclinical infections in pigs,in particular: Trypanosoma congolense simae, T. vivax vivax, T.congolense congolense, T. brucei evansi, Tritrichomonas suis,Trichomitus rotunda, Tetratrichomonas buttreyi, Eimeria debliecki, E.suis, E. scabra, E. perminuta, E. spinosa, E. polita, E. porci, E.neodebliecki, Isospora suis, Cryptosporidium, Toxoplasma gondii,Sarcocystis miescheriana, S. suihominis, Babesia trautmanni, B.perroncitoi, Balantidium coli.

[0134] The agricultural and breeding livestock include mammals such as,for example, cattle, horses, sheep, pigs, goats, camels, water buffalo,donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as,for example, mink, chinchilla, racoon, birds such as, for example,chicken, geese, turkeys, ducks, pigeons, bird species for keeping athome and in zoos. They also include useful and ornamental fish. Pigs ofall species, subspecies and breeds should be particularly emphasized inthis connection.

[0135] Laboratory and experimental animals include mice, rats, guineapigs, golden hamsters, dogs and cats.

[0136] Pets include dogs and cats.

[0137] The fish include useful, breeding, aquarium and ornamental fishof all ages which live in fresh and salt water. The useful and breedingfish include, for example, carp, eel, trout, white fish, salmon, bream,roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriolaquinqueradiata), Japanese eel (Anguilla japonica), red sea bream(Pagurus major), sea bass (Dicentrarchus labrax), grey mullet (Mugiluscephalus), pompano, gilthead sea bream (Sparus aurata), Tilapia spp.,chichlid species such as, for example, plagioscion, channel catfish. Thecompositions according to the invention are particularly suitable fortreating fry, for example carp with a body length of from 2 to 4 cm. Thecompositions are also very suitable in eel growing.

[0138] The following examples are intended to illustrate the inventionwithout, however, restricting it:

[0139] Investigations of the efficacy of ponazuril compared withtoltrazuril

[0140] A. Efficacy of ponazuril on artificially induced infections ofchickens with Eimeria tenella, E. maxima and E. acervulina:

[0141] The aim of this investigation was to test ponazuril for efficacyfor an artificial mixed infection (Eimeria tenella, E. maxima and E.acervulina) in chickens under cage housing conditions.

[0142] Groups each of 44 birds (4 replicates per treatment of 11 birdsin each case) were formed and, on day 14, infected with sporulatedoocysts. Ponazuril was administered each day on day 10-24 or 17-24.Three dosages in the feed were used in both treatment periods: 5 ppm, 10ppm and 20 ppm. The result of the treatment was determined by variousclinical and parasitological parameters, including the mortality causedby the coccidiosis and the oocyst excretion in the faeces.

[0143] The infection was moderate to extensive. The mortality caused bythe coccidiosis was 20% of the untreated controls. It was possible tocontrol the infection with all dosages and treatment schedules. Thedegree of control depended directly on the dosage and the start of thetreatment. An early start of the treatment reduced the parasitologicalfindings significantly (oocyst excretion and number of lesions) andimproved the technical parameters (body weight gain and feedconversion). The highest dosage (20 mg of ponazuril in the feed) showedthe best results. This dosage corresponded approximately to a dosage of3.5 mg/kg of body weight and day.

[0144] B. Field trial of the efficacy of ponazuril compared withtoltrazuril for the treatment of natural infections of grazing lambswith coccidiosis: Stock Group Treatment (species/ (infection/ Infection(formulation/ number/man- treatment) (parasite/route) dose) agement)Parameter 2 groups Infection with 5% w/v Sheep/ Oocyst treated Eimeriaspp. on suspension, 10 to 24 excretion, with the pasture 20 mg/kganimals per mortality, toltrazuril (principal species 5% w/v group (159consistency as drench E. ovinoidalis suspension, sheep in of the faeces,on day 7 and 10 and total)/field weight gain 3 groups E. crandallis)/ 20mg/kg trial treated infection with ponazuril as drench on day 7 3 groupsuntreated

[0145] The aim of the trials was to compare toltrazuril and ponazurilfor efficacy on natural infections with pathogens of the Eimeria family.

[0146] The active ingredients were compared in three consecutiveexperiments:

[0147] Experiment 1: untreated control—toltrazuril 20 mg/kg—ponazuril 20mg/kg

[0148] Experiment 2: untreated control—ponazuril 20 mg/kg

[0149] Experiment 3: untreated control—toltrazuril 20 mg/kg—ponazuril 10mg/kg.

[0150] The oocyst excretion and the consistency of the faeces were usedas main parameters. The weight of the stock was likewise checkedoccasionally.

[0151] The infection pressure was low during the period of theinvestigation. Both toltrazuril and ponazuril were completely effectiveunder the test conditions.

[0152] C: Efficacy of toltrazuril and ponazuril for the treatment ofexperimental infections of piglets with Isospora suis.

[0153] The aim of this trial was to investigate the efficacy of variousdosages of toltrazuril and ponazuril for piglet coccidiosis.

[0154] 2 groups (A and B) of 3-week old piglets were infected on day 0by stomach tube with 5×10³ oocysts of Isospora suis. Group C was kept asinfected, untreated control group.

[0155] All the groups received toltrazuril or ponazuril as single doseaccording to their individual body weight on day 3 after the infection.Group A I. toltrazuril 10 mg/kg of body weight II. toltrazuril 20 mg/kgof body weight Group B I. ponazuril 10 mg/kg of body weight II.ponazuril 20 mg/kg of body weight Group C no administration MacMastercoprological examination Day −3 0 3 4 5 6 7 9 11 13 15 17 19 21 GroupI. 1. − − − − − − − − − − − − − − A 2. − − − − − − − − − − − − − − 3. −− − − − − − − − − − − − − 4. − − − − − − − − − − − − − − II. 1. 2. − − −− − − − − − − − − − − 3. − − − − − − − − − − − − − − 4. − − − − − − − −− − − − − − Group I. 1. − − − − − − − − − − − − − − B 2. − − − − − − − −− − − − − − 3. − − − − − − − − − − − − − − 4. − − − − − − − − − − − − −− II. 1. − − − − − − − − − − − − − − 2. − − − − − − − − − − − − − − 3. −− − − − − − − − − − − − − 4. − − − − − − − − − − − − − − Group 1. − − −− − 0.2 0.3 4.8 38 72 74 78 48.8 12 C 2. − − − − − 0.3 0.3 1.1 46 9884.6 86 62.4 10 3. − − − − − − 0.2 1.8 57.5 102 98 88 46.8 9.6 4. − − −− − 0.1 0.4 5.6 61 144 116 82.4 38.8 7.2

[0156] Comparison of the toxicity of a sulphide (toltrazuril) with thecorresponding sulphone (ponazuril):

[0157] The following toxicity data were determined in accordance withOECD/GLP guidelines, in particular OECD 414, 401 and 408. Theinvestigations of the teratogenicity of the compounds was carried out inaccordance with the US guidelines—“Teratogenicity study”, Guidelines forRegistering Pesticides in the U.S.A., U.S. Environmental ProtectionAgency, Hazard Evaluation: Human and 10 Domestic Animals. U.S. -FederalRegister, Vol. 43, paragraph 163.83-3, adopted November 1982.Toltrazuril Ponazuril

Dosage NOEL mg/kg Dosage NOEL mg/kg Investigation (NOEL) of body weight(NOEL) of body weight LD50 rat, oral 1600-5000 mg/kg <1000 >5000 5000 ofbody weight Subchronic rat 0, 15, 60, 240 1.1 0, 50, 150, 250, 11.2 ppm1000, 4000 ppm Subchronic 0, 1.5, 4.5, 13.5 1.5 0, 200, 1000, 8.3 dogmg/kg of body 5000 ppm weight Teratogenicity 0, 1, 3, 10, 1.0 10, 30,90, 90 rat 30 mg/kg 300 mg/kg of of body weight body weightTeratogenicity 0, 0.5, 0.75, 1, 2, 2.0 10, 30, 90, 30 rabbit 3, 10 mg/kgof 300 mg/kg of body weight body weight

[0158] Preparation examples

[0159] General preparation method

[0160] The suspensions indicated below can be prepared by the followingmethods:

[0161] The substances are each stirred together until a homogeneoussuspension is produced, and the pH is adjusted to a desired range. Thebentonite or sodium alginate suspension stabilizer is macerated whereappropriate at about 80 or about 40° C. respectively. After preparationof the suspension it can be dispensed into suitable containers.

[0162] The amounts are indicated in the formulas in each case in grams[g].

EXAMPLE 1 (suspension)

[0163] Ponazuril microfme 10.0 Polyoxyl-35-castor oil 5.0 Methylp-hydroxybenzoate 0.075 Propyl p-hydroxybenzoate 0.025 Sodiumcarboxymethylcellulose 1.0 Water demin. ad 100.0 g

EXAMPLE 2 (suspension)

[0164] Ponazuril microfine 1.0 Methyl p-hydroxybenzoate 0.075 Propylp-hydroxybenzoate 0.025 Sodium alginate* 1.0 Water demin. ad 100.0 g

EXAMPLE 3 (suspension)

[0165] Ponazuril microfine 50.0 Bentonite** 3.5 Xanthan 3.0 Dioctylsodium sulphosuccinate 2.5 Simethicone emulsion 1.0 Sodium benzoate 2.0Sodium propionate 2.0 Citric acid powder 4.0-10.0 1,2-Propylene glycol105.0 Water demin. ad 1030.0 g The pH is adjusted to 3.4 to 4.2 byappropriate metering of citric acid.

Patent claims:
 1. Use of compounds of the formula (I)

in which R¹ represents halogenoalkyl, R² represents alkyl, alkoxy,halogen or SO₂N(CH₃)₂, and their physiologically tolerated salts, forcontrolling coccidiosis in livestock.
 2. Use of compounds of the formula(I) according to claim 1 for preparing anti- coccidiosis compositions.3. Use according to claim 1, characterized in that the compounds of theformula (I) according to claim 1 are administered in the form of anaqueous oral suspension.
 4. Composition for use according to claim 1,characterized in that it is an aqueous suspension, which can beadministered orally, of compounds of the formula (I) according toclaim
 1. 5. Composition according to claim 4, characterized in that itis an aqueous suspension.
 6. Composition according to claim 4,comprising: A) compounds of the formula (I) in concentrations of from0.1 to 30% by weight, particularly preferably from 1 to 10% by weight,B) suspension stabilizers such as, for example, bentonites and/orxanthans in concentrations each of from 0.01 to 5% by weight,particularly preferably from 0.05 to 1% by weight, C) where appropriateionic or nonionic wetting agents in concentrations of from 0.01 to 5% byweight, particularly preferably from 0.1 to 0.5% by weight, D) whereappropriate antifoams based, for example, on silicones in concentrationsof from 0.01 to 5% by weight, particularly preferably from 0.05 to 0.5%by weight, E) where appropriate humectants in concentrations of from 1to 30% by weight, particularly preferably from 5 to 20% by weight, F)where appropriate preservatives or else combinations thereof inconcentrations of from 0.001 to 5% by weight, particularly preferablyfrom 0.1 to 0.5% by weight, G) where appropriate acidic or basicsubstances in the concentrations necessary to adjust the pH,
 7. Methodfor controlling coccidiosis in livestock, characterized in that acomposition comprising a compound of formula (I) as defined in claim 1is administered to the relevant animal.